RESUMO
Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular-coerulear excitatory interactions in prenatally undernourished young-adult rats.
Assuntos
Hipertensão/patologia , Hipotálamo/metabolismo , Desnutrição/complicações , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Feminino , Frequência Cardíaca , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , RatosRESUMO
The ablation of renal nerves, by destroying both the sympathetic and afferent fibers, has been shown to be effective in lowering blood pressure in resistant hypertensive patients. However, experimental studies have reported that the removal of sympathetic fibers may lead to side effects, such as the impairment of compensatory cardiorenal responses during a hemodynamic challenge. In the present study, we evaluated the effects of the selective removal of renal afferent fibers on arterial hypertension, renal sympathetic nerve activity, and renal changes in a model of renovascular hypertension. After 4 weeks of clipping the left renal artery, afferent renal denervation (ARD) was performed by exposing the left renal nerve to a 33 mM capsaicin solution for 15 min. After 2 weeks of ARD, we found reduced MAP (~ 18%) and sympathoexcitation to both the ischemic and contralateral kidneys in the hypertensive group. Moreover, a reduction in reactive oxygen species was observed in the ischemic (76%) and contralateral (27%) kidneys in the 2K1C group. In addition, ARD normalized renal function markers and proteinuria and podocin in the contralateral kidney. Taken altogether, we show that the selective removal of afferent fibers is an effective method to reduce MAP and improve renal changes without compromising the function of renal sympathetic fibers in the 2K1C model. Renal afferent nerves may be a new target in neurogenic hypertension and renal dysfunction.
Assuntos
Vias Aferentes/fisiopatologia , Hipertensão Renovascular/fisiopatologia , Isquemia/fisiopatologia , Nefropatias/fisiopatologia , Rim/fisiopatologia , Animais , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Masculino , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Ratos , Ratos Wistar , Sistema Nervoso Simpático/fisiopatologiaRESUMO
PURPOSE: The pineal gland plays an important role in biological rhythms, circadian and circannual variations, which are key aspects in several headache disorders. OVERVIEW: Melatonin, the main pineal secreting hormone, has been extensively studied in primary and secondary headache disorders. Altered melatonin secretion occurs in many headache syndromes. Experimental data show pineal gland and melatonin both interfere in headache animal models, decreasing trigeminal activation. Melatonin has been shown to regulate CGRP and control its release. DISCUSSION: Melatonin has been used successfully as a treatment for migraine, cluster headaches and other headaches. There is a rationale for including the pineal gland as a relevant brain structure in the mechanisms of headache pathophysiology, and melatonin as a treatment option in primary headache.
Assuntos
Cefaleia/fisiopatologia , Glândula Pineal/fisiopatologia , Adulto , Animais , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Estudos de Casos e Controles , Criança , Ritmo Circadiano/fisiologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Método Duplo-Cego , Cefaleia/diagnóstico por imagem , Cefaleia/tratamento farmacológico , Cefaleia/patologia , Humanos , Melatonina/fisiologia , Melatonina/uso terapêutico , Oxirredução , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Glândula Pineal/metabolismo , Glândula Pineal/patologia , Receptores de Melatonina/agonistas , Receptores de Melatonina/fisiologia , Serotonina/metabolismo , Gânglio Cervical Superior/fisiopatologiaRESUMO
BACKGROUND: Thyroid hormone and leptin are essential regulators of energy homeostasis. Both hormones stimulate energy expenditure but have opposite effects on appetite. The mechanisms behind food intake regulation in thyroid dysfunctions are poorly understood. It has been shown that hypothyroid rats exhibited impaired leptin anorexigenic effect and signaling in total hypothalamus, even though they were hypophagic. It was hypothesized that hypothyroidism modulates the expression of neuropeptides: orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC), independently of inducing nuclei-specific changes in hypothalamic leptin signaling. METHODS: Adult male rats were rendered hypothyroid by administration of 0.03% methimazole in the drinking water for 21 days. Protein content of NPY, POMC, and leptin signaling (the signal transducer and activator of transcription 3 [STAT3] pathway) were evaluated by Western blot, and mRNA levels by real time reverse transcription polymerase chain reaction in arcuate (ARC), ventromedial (VMN), and paraventricular (PVN) hypothalamic nuclei isolated from euthyroid (eu) and hypothyroid (hypo) rats. Leptin anorexigenic effect was tested by recording food intake for two hours after intracerebroventricular (i.c.v.) administration of leptin. Statistical differences were considered significant at p ≤ 0.05. RESULTS: Hypothyroidism was confirmed by decreased serum triiodothyronine, thyroxine, and increased thyrotropin, in addition to increased levels of pro-TRH mRNA in PVN and Dio2 mRNA in the ARC of hypo rats. Hypothyroidism decreased body weight and food intake associated with decreased protein content of NPY and increased content of POMC in the ARC. Conversely, hypothyroidism induced central resistance to the acute anorexigenic effect of leptin, since while euthyroid rats displayed reduced food intake after leptin i.c.v. injection, hypothyroid rats showed no response. Hypothyroid rats exhibited decreased leptin receptor (ObRb) protein content in ARC and VMN but not in PVN nucleus. ObRb protein changes were concomitant with decreased phosphorylated STAT3 in the ARC, and decreased total STAT3 in VMN and PVN. However, hypothyroidism did not affect mRNA levels of Lepr or Stat3 in the hypothalamic nuclei. CONCLUSIONS: Experimental hypothyroidism induced a negative energy balance accompanied by decreased NPY and increased POMC protein content in the ARC, resulting in predominance of anorexigenic pathways, despite central leptin resistance and impairment of the leptin signaling cascade in a nuclei-specific manner.
Assuntos
Regulação do Apetite , Núcleo Arqueado do Hipotálamo/metabolismo , Comportamento Alimentar , Hipotireoidismo/metabolismo , Leptina/metabolismo , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/metabolismo , Transdução de Sinais , Animais , Núcleo Arqueado do Hipotálamo/fisiopatologia , Modelos Animais de Doenças , Ingestão de Alimentos , Metabolismo Energético , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/genética , Hipotireoidismo/fisiopatologia , Hipotireoidismo/psicologia , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Leptina/genética , Masculino , Metimazol , Neuropeptídeo Y/genética , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Fosforilação , Pró-Opiomelanocortina/genética , Ratos Wistar , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Hormônio Liberador de Tireotropina/genética , Hormônio Liberador de Tireotropina/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Núcleo Hipotalâmico Ventromedial/fisiopatologia , Redução de Peso , Iodotironina Desiodinase Tipo IIRESUMO
A high-salt diet can lead to hydromineral imbalance and increases in plasma sodium and osmolality. It is recognized as one of the major contributing factors for cardiovascular diseases such as hypertension. The paraventricular nucleus (PVN) plays a pivotal role in osmotically driven sympathoexcitation and high blood pressure, the precise mechanisms of which are not fully understood. Recent evidence indicates that AVP released from magnocellular neurons might be involved in this process. Using a combination of in vivo and in situ studies, we sought to investigate whether AVP, acting on PVN neurons, can change mean arterial pressure (MAP) and sympathetic nerve activity (SNA) in euhydrated male rats. Furthermore, we wanted to determine whether V1a receptors on PVN neurons would be involved in salt-induced sympathoexcitation and hypertension. In rats, 4 days of salt loading (NaCl 2%) elicited a significant increase in plasma osmolality (39 ± 7 mosmol/kgH2O), an increase in MAP (26 ± 2 mmHg, P < 0.001), and sympathoexcitation compared with euhydrated rats. Microinjection of AVP into the PVN of conscious euhydrated animals (100 nl, 3 µM) elicited a pressor response (14 ± 2 mmHg) and a significant increase in lumbar SNA (100 nl, 1 mM) (19 ± 5%). Pretreatment with a V1a receptor antagonist, microinjected bilaterally into the PVN of salt-loaded animals, elicited a decrease in lumbar SNA (-14 ± 5%) and MAP (-19 ± 5 mmHg), when compared with the euhydrated group. Our findings show that AVP plays an important role in modulating the salt-induced sympathoexcitation and high blood pressure, via V1a receptors, within the PVN of male rats. As such, V1a receptors in the PVN might contribute to neurogenic hypertension in individuals consuming a high-salt diet.
Assuntos
Arginina Vasopressina/metabolismo , Pressão Arterial , Hipertensão/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Vasopressinas/metabolismo , Cloreto de Sódio na Dieta , Sistema Nervoso Simpático/metabolismo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Arginina Vasopressina/administração & dosagem , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/etiologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Masculino , Microinjeções , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Ratos Wistar , Receptores de Vasopressinas/agonistas , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Fatores de TempoRESUMO
NEW FINDINGS: What is the topic of this review? This review addresses the underlying mechanisms involved in sympathoexcitation during renovascular hypertension, focusing on the importance of increased oxidative stress in the paraventricular nucleus and rostral ventrolateral medulla. What advances does it highlight? Whether renal or autonomic dysfunction is the major contributor to systemic hypertension following a renovascular insult is still a matter of debate. Here, we take an integrative approach by describing the crosstalk between the kidney and brain. We show how changes in the CNS, and in sympathetic premotor neurons in particular, are activated by ischaemic renal disease in an experimental model of renovascular hypertension. This review addresses the underlying mechanisms involved in the sympathoexcitation in renovascular hypertension. We focus on the importance of increased oxidative stress in the paraventricular nucleus of hypothalamus (PVN) and rostral ventrolateral medulla (RVLM) for the autonomic dysfunction associated with renovascular hypertension in the two-kidney, one-clip (2K-1C) model. We found in 2K-1C rats, 6 weeks after clipping, a significant increase in the mRNA and protein expression of the angiotensin II type 1 receptor within the RVLM and PVN. In addition, mRNA from NADPH oxidase subunits (p47phox and gp91phox) was greater in the RVLM and PVN of 2K-1C rats than in a sham-operated group. However, CuZn superoxide dismutase gene expression in these regions was not changed, suggesting that excessive production of reactive oxygen species overwhelms any endogenous antioxidant system in the RVLM and PVN in renovascular hypertension. In fact, acute administration of tempol or vitamin C (either i.v. or directly into the PVN or RVLM) caused a significant decrease in blood pressure and renal sympathetic nerve activity in 2K-1C rats, but not in control animals. Thus, we suggest that an increase in the activity of RVLM and PVN neurons triggered by angiotensin II and oxidative stress is a major mechanism involved in the maintenance of sympathoexcitation of the cardiovascular system in renovascular hypertension.
Assuntos
Hipertensão Renovascular/metabolismo , Rim/inervação , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Humanos , Hipertensão Renovascular/fisiopatologia , Estresse Oxidativo/fisiologiaRESUMO
Background: In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats. Objective: Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABAB receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats. Methods: Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABAB receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1mA/10s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal. Results: No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABAB receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. Conclusion: Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN. .
Fundamento: Distúrbios da motilidade do intestino proximal no infarto agudo do miocárdio podem desencadear sintomas digestivos como náuseas e vômitos. O infarto do miocárdio ocasiona retardo do esvaziamento gástrico (EG) de líquido em ratos. Objetivo: Investigar se existe a influência do nervo vago (VGX), adrenoreceptores α-1, receptores GABAB do sistema nervoso central e participação do núcleo paraventricular (NPV) do hipotálamo no esvaziamento gástrico (EG) e complacência gástrica (CG) em ratos infartados. Métodos: Ratos Wistar (n = 8-15) foram divididos em: grupo infarto (INF), sham (SH) e subdivididos. O infarto foi realizado por ligadura da artéria coronária descendente anterior. A complacência gástrica foi estimada com curvas pressão-volume. Realizada vagotomia por secção dos ramos dorsal e ventral. Para verificar a ação dos receptores GABAB foi injetado baclofeno por via intra ventrículo-cerebral. Simpatectomia química foi realizada com prazosina intravenosa (iv), e na lesão do núcleo paraventricular do hipotálamo foi utilizada corrente elétrica de 1mA/10s, com esvaziamento gástrico determinado por medição da retenção gástrica (% RG) de uma refeição salina. Resultados: Não houve diferença significativa na CG. A vagotomia (VGX) reduziu significativamente a %RG; no grupo INF, o tratamento intra ventrículo-cerebral (ivc) com baclofeno reduziu significativamente a % RG; não houve conclusivamente envolvimento dos receptores GABAB em retardar o EG; o tratamento intravenoso com prazosina reduziu significativamente a %RG no grupo INF. A lesão do NPV aboliu o efeito do infarto do miocárdio no EG. Conclusão: O nervo vago, receptores α-adrenérgicos e núcleo paraventricular estão envolvidos no retardo do esvaziamento gástrico no infarto agudo do miocárdio em ratos. .
Assuntos
Animais , Masculino , Esvaziamento Gástrico/fisiologia , Infarto do Miocárdio/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Receptores Adrenérgicos alfa 1/fisiologia , Receptores de GABA-B/fisiologia , Nervo Vago/fisiopatologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Baclofeno/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Gastroparesia/fisiopatologia , Infarto do Miocárdio/complicações , Prazosina/farmacologia , Ratos Wistar , Fatores de Tempo , VagotomiaRESUMO
BACKGROUND: In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats. OBJECTIVE: Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABAB receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats. METHODS: Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABAB receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1 mA/10 s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal. RESULTS: No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABAB receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. CONCLUSION: Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN.
Assuntos
Esvaziamento Gástrico/fisiologia , Infarto do Miocárdio/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Receptores Adrenérgicos alfa 1/fisiologia , Receptores de GABA-B/fisiologia , Nervo Vago/fisiopatologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Baclofeno/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Gastroparesia/fisiopatologia , Masculino , Infarto do Miocárdio/complicações , Prazosina/farmacologia , Ratos Wistar , Fatores de Tempo , VagotomiaRESUMO
Chronic short sleep duration has been linked to sympathoexcitation and increased risk of cardiovascular disease. The central nervous system plays an important role in the regulation of sympathetic activity. Thus, the present study evaluates the pre-autonomic neurones in the paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla after sleep restriction using various protein expression measurements and electrophysiological approaches. Wistar male rats were assigned randomly to two experimental groups: control or sleep restriction for 14 days. Sleep restriction was defined as 20 h of paradoxical sleep deprivation followed by a 4 h sleep permission period using the modified multiple platform method. Micropunches of the paraventricular nucleus of the hypothalamus and rostral ventrolateral medulla were dissected to evaluate the protein expression of angiotensin II receptor, type 1 (AT1), AT2, gamma aminobutyric acidA ) (N-methyl-d-aspartate receptor1) and neuronal nitric oxide synthase neuronal nitric oxide synthase isoform through immunoblotting. Sleep restriction induced a down-regulation of the gamma aminobutyric acidA receptor in the paraventricular nucleus of the hypothalamus. Microinjection of bicuculline, a gamma aminobutyric acid receptor blocker, into the paraventricular nucleus of the hypothalamus increased renal sympathetic activity renal sympathetic nerve activity, mean arterial pressure and heart rate in anaesthetized control rats. However, the amplitude and frequency of renal sympathetic nerve activity was higher in the sleep restriction group. These findings suggest that gamma aminobutyric acidergic inhibition within the paraventricular nucleus of the hypothalamus is involved in sympathoexcitation induced by sleep restriction.
Assuntos
Pressão Sanguínea , Frequência Cardíaca , Núcleo Hipotalâmico Paraventricular/metabolismo , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Sistema Nervoso Simpático/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Bicuculina/administração & dosagem , Bicuculina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Regulação para Baixo , Frequência Cardíaca/efeitos dos fármacos , Rim/inervação , Rim/metabolismo , Masculino , Bulbo/metabolismo , Bulbo/fisiopatologia , Microinjeções , Óxido Nítrico Sintase Tipo I/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sistema Nervoso Simpático/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Ácido gama-Aminobutírico/efeitos dos fármacosRESUMO
We showed previously that sino-aortic denervation prevented training-induced plasticity in pre-autonomic oxytocinergic neurons and blocked the beneficial effects of training. In this study, we investigate the combined effect of training and removal of specific chemoreceptor afferents on both cardiovascular parameters and oxytocin (OT) gene and protein expression within the hypothalamic paraventricular nucleus (PVN). Wistar rats and spontaneously hypertensive rats (SHRs) underwent carotid body denervation or sham surgery and were trained or kept sedentary for 3 months. After haemodynamic measurements at rest, rats were anaesthetized for brain perfusion. Fresh (perfused with PBS) and fixed brains (perfused with 4% paraformaldehyde) were processed for PVN OT mRNA (real-time PCR) and OT immunoreactivity within PVN subnuclei. In sham-operated rats, training improved treadmill performance and reduced resting heart rate (Wistar, -8%; SHRs, -10%), with a reduction in blood pressure only in SHRs (-8%). Training was accompanied by increased PVN OT mRNA expression (twofold increase in sham-operated SHRs) and peptide density in the posterior, ventromedial and dorsal cap PVN subnuclei (on average 70% increase in both strains), with significant correlations between OT content and training-induced resting bradycardia in sham-operated groups. Carotid body denervation did not interfere with the performance gain, abolished chemoreflex activation (without changing baroreflex control) and blocked training-induced cardiovascular adaptations and training-induced changes in PVN OT content in both strains. After carotid body denervation, there was no correlation between OT mRNA or OT immunoractivity and resting heart rate. The chronic absence of chemoreceptor inputs uncovers an unknown role of chemoreceptor signalling in driving the plasticity/activity of PVN oxytocinergic pre-autonomic neurons, thus mediating training-induced cardiovascular adaptive responses.
Assuntos
Corpo Carotídeo/metabolismo , Hipertensão/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Esforço Físico , Adaptação Fisiológica , Animais , Denervação Autônoma , Barorreflexo , Pressão Sanguínea , Modelos Animais de Doenças , Regulação da Expressão Gênica , Frequência Cardíaca , Hipertensão/genética , Hipertensão/fisiopatologia , Imuno-Histoquímica , Masculino , Ocitocina/genética , Núcleo Hipotalâmico Paraventricular/fisiopatologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Comportamento Sedentário , Transdução de Sinais , Fatores de TempoRESUMO
The paraventricular nucleus (PVN) of the hypothalamus is an important region of the brain involved in the regulation of sympathetic vasomotor tone. Accumulating evidence supports the idea that a change in hypothalamic γ-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory inputs contribute to the exacerbated sympathetic drive in chronic heart failure (HF). The purpose of this study was to determine whether a possible imbalance between glutamatergic and GABAergic inputs to the PVN contributes to increased sympathetic outflow in HF in two different sympathetic territories. Renal (RSNA) and splanchnic sympathetic nerve activity (SSNA), mean arterial blood pressure (MAP) and heart rate were recorded from urethane-anesthetized HF or sham rats. The NMDA-glutamate and GABA-A receptor densities within the PVN were quantified in HF and sham rats by autoradiography. Bilateral microinjection of kynurenic acid (4nmol) into the PVN decreased MAP and RSNA and SSNA in HF but not in sham rats. Furthermore, in response to GABA-A blockade in the PVN by bicuculline (400 pmol), hypertension and SSNA were reduced in HF compared to sham. The quantification of ionotropic NMDA receptors and GABA-A receptors in the PVN showed a significant reduction of GABA-A in HF rats; however, the NMDA density in the PVN did not differ between groups. Thus, this study provides evidence that the sympathoexcitation is maintained by an imbalance between GABAergic and glutamatergic inputs in the PVN in HF. The reduced GABAergic input results in relatively augmented glutamatergic actions in the PVN of HF rats.
Assuntos
Pressão Sanguínea/fisiologia , Neurônios GABAérgicos/fisiologia , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Nervos Esplâncnicos/fisiopatologia , Animais , Autorradiografia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacocinética , Ecocardiografia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Receptores de GABA-A/farmacocinética , Neurônios GABAérgicos/efeitos dos fármacos , Insuficiência Cardíaca/patologia , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Rim/inervação , Ácido Cinurênico/farmacologia , Ligadura/efeitos adversos , Masculino , Microinjeções , Muscimol/farmacocinética , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Floroglucinol/análogos & derivados , Floroglucinol/farmacocinética , Ratos , Ratos Wistar , Nervos Esplâncnicos/efeitos dos fármacos , Terpenos/farmacocinética , Trítio/farmacocinéticaRESUMO
The present study investigated whether nitric oxide (NO)-producing neurons localized in brain areas related to anxiety are also activated after ethanol withdrawal. Male Wistar rats were subjected to an oral ethanol self-administration procedure, in which they were offered 6-8% (vol/vol) ethanol solution for a period of 21 days followed by abrupt discontinuation of the treatment. Control animals received control dietary fluid for similar periods of time. Twenty-four or 48 h after ethanol discontinuation, the animals were exposed to the open field for 10 min. Two hours later, their brains were removed and processed for Fos immunohistochemistry and nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry (which is used to detect NO-producing neurons). Decreased exploratory activity was observed in animals subjected to 24-h withdrawal, characterized by a shorter distance traveled in the open field. Additionally, increased Fos expression was detected in brain areas, such as the cingulate and piriform cortices, several hypothalamic nuclei, amygdaloid nuclei, most subdivisions of the periaqueductal gray matter, and dorsal raphe nucleus (DRN). Ethanol withdrawal activated NO-producing neurons in the paraventricular nucleus (PVN) of the hypothalamus, dorsolateral periaqueductal gray matter (DLPAG), and DRN. The results show that ethanol withdrawal activates NO-producing neurons in the PVN, DLPAG, and DRN, which are brain areas implicated in the modulation of emotional, autonomic, and motor expression of anxiety-like behaviors.
Assuntos
Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Etanol/administração & dosagem , Neurônios/fisiologia , Óxido Nítrico/biossíntese , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Imuno-Histoquímica , Masculino , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Substância Cinzenta Periaquedutal/fisiopatologia , Núcleos da Rafe/fisiopatologia , Ratos , Ratos WistarRESUMO
We investigated the effects of electrolytic damage to the central nucleus of the amygdala on brain c-fos expression and 0.3 M NaCl intake of adult male rats (n = 6-12/group) submitted to a cycle of 36 h of water deprivation (WD) followed by 2 h water intake until satiety or partial rehydration (PR). The groups were divided into sham lesion (CEAs), bilateral lesion of the CEA (CEAX) and misplaced lesion with intact CEA (CEAm). The WD-PR produced a marked increase in c-fos expression in the medial parabrachial nucleus (MPBN) and some increase in the parvocelullar portion of the hypothalamic paraventricular nucleus (PVNp), compared to respective hydrated control (no water deprivation) state in CEAX, but not in CEAs or CEAm. The WD-PR induced similar c-fos expression in the lamina terminalis, supraoptic nucleus, magnocellular PVN and lateral parabrachial nucleus in both CEAX and CEAs. The CEAX showed the typical reduced daily need-free 0.3 M NaCl intake compared to CEAs. However, the 0.3 M NaCl intake of CEAX, unexpectedly, was not significantly different from CEAs or intact rats in the sodium appetite test that followed a cycle of WD-PR. The results do not allow associating the alterations in c-fos expression to the typical inhibition of sodium appetite well known in the literature to be produced by damage to the CEA. Nevertheless, the enhanced cell activation in the MPBN and PVNp suggests an inhibitory role for the CEA on the activity of these nuclei when water-deprived rats have quenched their thirst.
Assuntos
Tonsila do Cerebelo/lesões , Tonsila do Cerebelo/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Privação de Água/fisiologia , Animais , Análise Química do Sangue , Encéfalo/fisiopatologia , Comportamento de Ingestão de Líquido/fisiologia , Imuno-Histoquímica , Masculino , Neurônios/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio , ÁguaRESUMO
Glucocorticoids have major effects on food intake, demonstrated by the decrease of food intake following adrenalectomy. Satiety signals are relayed to the nucleus of the solitary tract (NTS), which has reciprocal projections with the arcuate nucleus (ARC) and paraventricular nucleus (PVN) of the hypothalamus. We evaluated the effects of glucocorticoids on the activation of hypothalamic and NTS neurons induced by food intake in rats subjected to adrenalectomy (ADX) or sham surgery 7 days before the experiments. One-half of ADX animals received corticosterone (ADX+B) in the drinking water (B: 25 mg/l). Fos/tyrosine hydroxylase (TH), Fos/corticotrophin-releasing factor (CRF) and Fos immunoreactivity were assessed in the NTS, PVN, and ARC, respectively. Food intake and body weight were reduced in the ADX group compared with sham and ADX+B groups. Fos and Fos/TH in the NTS, Fos, and Fos/CRF immunoreactive neurons in the PVN and Fos in the ARC were increased after refeeding, with higher number in the ADX group, compared with sham and ADX+B groups. CCK administration showed no hypophagic effect on ADX group despite a similar increase of Fos/TH immunoreactive neurons in the NTS compared with sham and ADX+B groups, suggesting that CCK alone cannot further increase the anorexigenic effect induced by glucocorticoid deficiency. The present data indicate that glucocorticoid withdrawal reduced food intake, which was associated with higher activation of ARC, CRF neurons of the PVN, and catecholaminergic neurons of the NTS. In the absence of glucocorticoids, satiety signals elicited during a meal lead to an augmented activation of brain stem and hypothalamic pathways.
Assuntos
Comportamento Animal , Ingestão de Alimentos , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Glucocorticoides/deficiência , Hipotálamo/fisiopatologia , Resposta de Saciedade , Núcleo Solitário/fisiopatologia , Adrenalectomia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/fisiopatologia , Peso Corporal , Catecolaminas/metabolismo , Colecistocinina/administração & dosagem , Corticosterona/administração & dosagem , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Ingestão de Líquidos , Jejum , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Hipotálamo/metabolismo , Masculino , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Neurônios/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Núcleo Solitário/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Effects of different parameters of hypothalamic paraventricular nucleus (PVN) electrical stimulation on somatic responses, in dorsal horn neurons were examined. In anaesthetized rats, single-unit extracellular recordings were made from dorsal horn lumbar segments, which receive afferent input from the toe and hind paw regions. We compared the neuronal responses evoked by electrical stimulation of the receptive field (RF) with the responses preceded by ipsilateral PVN stimulation. Only the responses corresponding to Adelta and C-fiber activation were inhibited when PVN stimulation was delivered. Fast-evoked responses corresponding to Abeta fibers were not modified. The magnitude of inhibition depends on the intensity and duration of the PVN stimulation train and gradually decreases as the time interval between the PVN and RF stimulations increases. The results indicate that PVN modulates nociceptive, but not non-nociceptive neuronal responses at the spinal cord level, and this modulation depends on the parameters of the stimulus utilized to activate PVN neurons.
Assuntos
Dor/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Células do Corno Posterior/fisiologia , Animais , Estimulação Elétrica , Masculino , Ratos , Ratos WistarRESUMO
Due to upward resetting of baroreceptors, tachycardia coexists with increased pressure during dynamic exercise. This review critically evaluates current knowledge of proposed mechanisms to explain the continuous resetting of baroreflex control of heart rate and sympathetic nerve activity during and after exercise and exercise training. Of interest is the exercise-induced upward resetting that occurs in hypertensive and normotensive individuals. Accumulated evidence indicates that not only somatosensory afferents, but also inputs from central command projecting to the nucleus tractus solitarius (NTS) in the dorsal brainstem may mediate inhibition of excitatory neurotransmission on barosensitive neurons. Specific coordinated activation of vasopressinergic and oxytocinergic projections to the NTS is essential to tonically maintain baroreflex sensitivity and to adjust heart rate and cardiac output to circulatory demand at rest and during exercise in both sedentary and trained individuals. These findings reinforce the paramount importance of the NTS in integration of cardiovascular control during exercise.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Exercício Físico , Hipertensão/fisiopatologia , Núcleo Solitário/fisiopatologia , Animais , Humanos , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Prenatal undernutrition is known to disturb the hypothalamo-pituitary-adrenal (HPA) axis, possibly through the programming of decreased expression of hypothalamic and pituitary glucocorticoid receptors. To test this hypothesis, we examined the corticosterone response to moderate subcutaneous (100 microg/kg) and intra-paraventricular (50 pmol, bilaterally) dexamethasone (DEX) challenges in normal eutrophic and prenatally undernourished young rats. Undernutrition was induced during fetal life by restricting the diet of pregnant mothers to 10 g daily, while mothers of eutrophic rats received the same diet ad libitum. At day 40 of postnatal life (i) undernourished rats showed increased plasma corticosterone concentration compared to normals; and (ii) subcutaneous and intra-paraventricular administrations of DEX led to reduced corticosterone levels in normal and undernourished animals, the effect of DEX (administered either peripherally or centrally) being significantly lower in the latter group. Results suggest that the low sensitivity of the HPA axis to DEX as well as the increased plasma corticosterone observed in prenatally undernourished rats could be due to the already reported glucocorticoid receptor underexpression found in the hypothalamus and pituitary of in utero undernourished animals, but alternative explanations involving central noradrenergic adaptive changes could also be possible.
Assuntos
Corticosterona/metabolismo , Doenças do Sistema Endócrino/fisiopatologia , Transtornos da Nutrição Fetal/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores de Glucocorticoides/metabolismo , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Corticosterona/sangue , Dexametasona/farmacologia , Doenças do Sistema Endócrino/etiologia , Feminino , Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Injeções Subcutâneas , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Ratos , Ratos Wistar , Receptores de Glucocorticoides/efeitos dos fármacosRESUMO
Activation of oxytocin (OT)ergic projections from the hypothalamic paraventricular nucleus (PVN) to the nucleus tractus solitarii contributes to cardiovascular adjustments during exercise training (EXT). Moreover, a deficit in this central OTergic pathway is associated with altered cardiovascular function in hypertension. Since PVN catecholaminergic inputs, known to be activated during EXT, modulate PVN cardiovascular-related functions, we aimed here to determine whether remodeling of PVN (nor)adrenergic innervation occurs during EXT and whether this phenomenon is affected by hypertension. Confocal immunofluorescence microscopy and tract tracing were used to quantify changes in (nor)adrenergic innervation density in PVN subnuclei and in identified dorsal vagal complex (DVC) projecting neurons (PVN-DVC) in EXT normotensive [Wistar-Kyoto rat (WKY)] and hypertensive [spontaneously hypertensive rat (SHR)] rats. In WKY, EXT increased the density of PVN dopamine beta-hydroxylase immunoreactivity (DBHir) (160%). Furthermore, the number and density of DBHir boutons overlapping PVN-DVC OTergic neurons were also increased during EXT (130%), effects that were blunted in SHR. Conversely, while DBHir in the medial parvocellular subnucleus (an area enriched in corticotropin-releasing hormone neurons) was not changed by EXT in WKY, a diminished DBHir was observed in trained SHR. Overall, these data support the concept that the PVN (nor)adrenergic innervation undergoes plastic remodeling during EXT, an effect that is differentially affected during hypertension. The functional implications of PVN (nor)adrenergic remodeling in relation to the central peptidergic control of cardiovascular function during EXT are discussed.
Assuntos
Fibras Adrenérgicas/metabolismo , Catecolaminas/metabolismo , Hipertensão/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Condicionamento Físico Animal/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Hipertensão/metabolismo , Imuno-Histoquímica , Masculino , Microscopia de Fluorescência , Plasticidade Neuronal , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Especificidade da EspécieRESUMO
Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 microg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 microg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel ("warmth receptor"). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 ("cold receptor"). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock.
Assuntos
Hipotálamo/efeitos dos fármacos , Hipotálamo/fisiopatologia , Choque Séptico/fisiopatologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/fisiologia , Temperatura Baixa , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Núcleo Hipotalâmico Dorsomedial/lesões , Núcleo Hipotalâmico Dorsomedial/patologia , Núcleo Hipotalâmico Dorsomedial/fisiopatologia , Relação Dose-Resposta a Droga , Temperatura Alta , Humanos , Hipotálamo/lesões , Hipotálamo/patologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/lesões , Núcleo Hipotalâmico Paraventricular/patologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/lesões , Área Pré-Óptica/patologia , Área Pré-Óptica/fisiopatologia , Ratos , Ratos Wistar , Choque Séptico/patologia , Choque Séptico/psicologiaRESUMO
The aim of this study was to assess the role of cholinergic transmission in the paraventricular nucleus of the hypothalamus (PVN) and carotid body receptors in mediating a rise in plasma glucose levels in response to hemorrhagic hypotension in rats. Methylatropine (1x10(-9) mol) or 0.15 M NaCl (0.2 microl) was injected into the PVN of Wistar rats weighing 250-300 g bearing a chronic jugular catheter for blood sampling and hemorrhage (1.2 ml/100 g/2 min). Polyethylene cannulae (PE-10) were inserted into the left femoral artery for cardiovascular monitoring. In the other experimental protocol, hemorrhage was performed on rats submitted to bilateral carotid receptor denervation (H-CD). The results show that the hyperglycemic response to hemorrhage was decreased by either methylatropine (H-MA) treatment or bilateral carotid receptor denervation (10.3+/-0.4 mM, control, n=15 vs. 7.7+/-0.2 mM, H-MA, n=12, and 7.6+/-0.3 mM, H-CD, n=5, p<0.01). Furthermore, methylatropine did not affect the recovery of blood pressure after hemorrhage-induced hypotension, suggesting that the metabolic and pressor adjustments have different efferent pathways. Our data demonstrate that cholinergic input from the PVN and carotid receptors (chemo- and/or baroreceptors) might participate in the same neural pathway activated by hemorrhage-induced hypotension that produces hyperglycemia.